Osteoporosis is a common disabling bone disease, particularly in post-menopausal women. Gradual loss of bone makes it porous and weak. Fracture of spine, hip and forearm frequently develop even without significant trauma.
Once the osteoporotic disease has developed, so much bone mass may already have been lost such that treatments directed at preventing further bone loss (for example, calcium supplements) would likely be of limited value. An ideal goal of therapy is patients with established osteoporosis with fracture is to provide a treatment program that will increase bone mass and restore "lost" bone. Unfortunately, most available treatment programs have failed to augment bone mass (Pak, The Menopause, Edit. J. J. Buchsbaum Springer-Verlag, 1983, pp. 35-54).
Sodium fluoride may be one agent capable of making more bone in osteoporosis. This possibility was first recognized in 1932, when Moller and Gudjonsson noted skeletal sclerosis in subject with overexposure with cryolite rich in fluoride (Acta Radiol., Vol. 13, 1932, pp. 269-294). It is now known that fluoride causes proliferation and increases the activity of osteoblasts, cells responsible for bone formation (Farley et al., Science, Vol. 222, 1983, pp. 330-332). When fluoride alone is given to patients with esteoporosis, the newly-formed bone is poorly mineralized (that is, deficient in calcium phosphate). However, when adequate calcium supplementation is provided along with fluoride, formation of mineralized bone may be stimulated (Jowsey et al., Amer. J. Med., Vol. 53, 1972, pp. 43-49). Using sodium fluoride (50-60 mg/day) with calcium supplement (800-1500 mg elemental calcium/day), formation of new bone has been shown on actual microscopic examination of biopsied bone (Briancon and Meunier, Orthop. Clin. North Amer., Vol. 12, 1981, pp. 629-648). Moreover, the rate of bone fracture was shown to be significantly reduced by treatment, compared to that of the untreated group (Riggs et al., N. Engl. J. Med., Vol. 306, 1982, pp. 446-450). Thus, there are sufficient references to suggest that long-term treatment with sodium fluoride could be effective in treating established osteoporosis.
Unfortunately, sodium fluoride has been associated with frequent adverse reactions. In several long-term trials, gastrointestinal side-effects (nausea, vomiting, diarrhea, bleeding) occurred in 16-50% of patients and rheumatic complications (painful foot and knee due to synovitis and plantar fascial syndrome) occurred in 17-32% (Table 1).
TABLE 1 ______________________________________ SIDE EFFECTS OF CONVENTIONAL SODIUM FLUORIDE Percentage of Side Effects Authors Patients ______________________________________ Gastrointestinal Riggs et al. (1980) 19.4 Riggs et al. (1982) 16.4 Briancon and 21.5 Meunier (1981) von Kesteren et al. 50.0 (1982) Rheumatic Riggs et al. (1980) 30.6 Riggs et al. (1982) 23.0 Briancon and 32.4 Meunier (1981) Franke et al. 17.4 (1974) ______________________________________
These complications have precluded the widespread acceptance of sodium fluoride for the treatment of osteoporosis. It should be noted that above clinical trials were conducted with plain or acid resistant form of sodium fluoride. To the best of our knowledge, a slow-release form of sodium fluoride, as embodied in this invention, has never been used for the long-term treatment of osteoporosis.
It is our contention that the special embodiments of our invention conferring slow-release characteristic to the oral sodium fluoride preparations result in protection against above-mentioned side effects of conventional preparations so far used, while providing sufficient fluoride absorption to confer beneficial effect on bone. Evidence for this contention will be provided in this continuation-in-part in the following section (Special Embodiment . . .) and illustrated by Examples to follow.